[Federal Register Volume 63, Number 129 (Tuesday, July 7, 1998)]
[Notices]
[Pages 36681-36686]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-17808]


-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[PF-814; FRL-5795-6]


Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: This notice announces the initial filing of pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-814, must 
be received on or before August 6, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically to: <a href="/cdn-cgi/l/email-protection#5837282875523c373b333d2c183d283935393134763d2839763f372e">opp-
<span class="__cf_email__" data-cfemail="25414a464e40516540554448444c490b4055440b424a53">[email protected]</span></a>. Follow the instructions under ``SUPPLEMENTARY 
INFORMATION.'' No confidential business information should be submitted 
through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public inspection in Rm. 1132 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

------------------------------------------------------------------------
                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Bipin Gandhi (PM 5)...........  Rm. 4W53, CS #2, 703-   1921 Jefferson  
                                 308-8380, e-            Davis Hwy,     
                                 mail:<a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="7b1c1a151f13125519120b12153b1e0b1a">[email protected]</a>   Arlington, VA  
                                 mail.epa.gov.                          
Cynthia Giles-Parker (PM 22)..  Rm. 229, CM #2, 703-    Do.             
                                 305-7740, e-mail:                      
                                 <a href="/cdn-cgi/l/email-protection#1a7d73767f6937106a7b68717f68347963746e72737b5a7f6a7b777b731076347f6a7b347d756c">giles-
<span class="__cf_email__" data-cfemail="473726352c223569243e29332f2e26072237262a262e">[email protected]</span>
l.epa.gov</a>.                             
------------------------------------------------------------------------

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice of filing, as well as the 
public version, has been established for this notice of filing under 
docket control number [PF-814] (including comments and data submitted 
electronically as described below). A public version of this record, 
including printed, paper versions of electronic comments, which does 
not include any information claimed as CBI, is available for inspection 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The official record is located at the address in 
``ADDRESSES'' at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    <a href="/cdn-cgi/l/email-protection#600f10104d040f030b0514200510010d01090c4e0510014e070f16"><span class="__cf_email__" data-cfemail="81eef1f1ace5eee2eae4f5c1e4f1e0ece0e8edafe4f1e0afe6eef7">[email protected]</span></a>


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comment and data 
will also be accepted on disks in Wordperfect 5.1 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket number (insert docket number) and appropriate 
petition number. Electronic comments on notice may be filed online at 
many Federal Depository Libraries.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives, 
Feed additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: June 24,1998.

Peter Caulkins, Acting

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required by section 408(d)(3) of the FFDCA. The summaries of the 
petitions were prepared by the petitioners and represent the views of 
the petitioners. EPA is publishing the petition summaries verbatim 
without editing them in any way. The petition summary announces the 
availability of a description of the analytical methods available to 
EPA for the detection and measurement of the pesticide chemical 
residues or an explanation of why no such method is needed.

1. Rhodia Inc.

PP 6E4714

    EPA has received a pesticide petition (PP 6E4714) from Rhodia Inc., 
CN 7500 Cranbury NJ 08512-7500 proposing pursuant to section 408(d) of 
the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 
40 CFR 180.1001 to establish an exemption from the requirement of a 
tolerance for Sucroglycerides derived from 21 CFR-approved fats and 
oils in or on the raw agricultural commodity after harvest. EPA has 
determined that the petition contains data or information regarding the 
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data supports granting of

[[Page 36682]]

the petition. Additional data may be needed before EPA rules on the 
petition.

A. Toxicological Profile

    As part of the EPA policy statement on inert ingredients published 
in the Federal Register of April 22, 1987 (52 FR 13305) (FRL 3190-1), 
the Agency set forth a list of studies which would generally be used to 
evaluate the risks posed by the presence of an inert ingredient in a 
pesticide formulation. However, where it can be determined without that 
data that the inert ingredient will present minimal or no risk, the 
Agency generally does not require some or all of the listed studies to 
rule on the proposed tolerance or exemption from the requirement of a 
tolerance for an inert ingredient.
    The data we believe supports establishing an exemption from 
tolerances is summarized below. More detailed information has been 
provided to the Agency in previous submissions.
    Sucroglycerides are a mixture of substances, primarily of mono- and 
di-glycerides and sucrose esters of fatty acids. The product is 
produced through a process of transesterification of an edible fat or 
oil with sucrose in the presence of a solvent. The resulting crude 
mixture is purified by vacuum distillation, counter-current extraction, 
and further distillation to remove solvent and other impurities.
    Rhodia has conducted studies on the physicochemical characteristics 
of a sucroglyceride derived from palm oil. The studies evaluated the 
product chemistry, solubility, and the octanol/water partition 
coefficient of sucroglycerides.
    1. Acute toxicity. The LD<INF>50</INF> of palm oil-derived 
sucroglyceride is estimated to be greater than 30 grams/kg. In 
addition, early studies of sucroglycerides use in the diets of bottle-
feeding calves indicated a lack of toxic response and an increased 
weight gain and improved food utilization.
    Sucrose esters of fatty acids are approved for food use and mono- 
and di-glycerides are GRAS-approved additives; sucroglycerides are 
GRAS-approved and approved for food use in Europe; sucrose esters of 
fatty acids and mono- and di-glycerides are unlikely to be dermally 
absorbed.
    Preliminary attempts to examine the potential environmental 
toxicity of Sucroglycerides have been made, but were not possible due 
to the physicochemical properties of the material. Sucroglycerides have 
the consistency of wax at low temperatures and petroleum jelly when 
warmed. In addition, as can be seen from the determination of the 
octanol/water partition coefficient, sucroglycerides are not water 
soluble (estimated Ko/w > 3.38 x 106), thereby precluding aquatic 
toxicity testing.
    2. Genotoxicty. The components of sucroglycerides already have 
regulatory acceptance as agricultural inerts exempted from tolerance; 
sucroglycerides are a complex mixture of sucrose esters of fatty acids 
and mono- and di-glycerides derived from FDA-approved edible fats and 
oils. None of the components of sucroglycerides are genotoxic.
    3. Reproductive and developmental toxicity. An early study of the 
potential effects of Sucroglycerides on reproduction in rats indicated 
that there were no effects on reproduction, pup survival and 
development, or pup anomalies at dietary dose levels up to 2%.
    4. Subchronic toxicity. In 1980 a 13-week subchronic toxicity study 
of Sucroglycerides with an 8-week ``recovery period'' was conducted in 
beagle dogs. This study utilized doses as high as 20% of the total 
dietary intake. Decrease body weight gains (bwt) were observed in the 
10% and 20% dose groups. These animals showed a significant weight gain 
recovery during the post-treatment period. No dose-related changes were 
noted in hematology, urinalysis, ophthalmoscopy, gross pathology or 
organ weights. Increased alkaline phosphatase and SGPT levels and fatty 
changes in the liver were noted for some animals in the high dose 
group, but most returned to normal during the recovery phase. Results 
should be interpreted keeping in mind that 20% of sucroglycerides in 
the diet represents a significant change in the normal dietary 
composition and could possibly cause changes in the nutritional status 
of the animals.
    5. Chronic toxicity. A chronic toxicity/carcinogenicity study of 
Sucroglycerides was conducted in rats in 1982. Sprague-Dawley rats 
received 0%, 5%, 10%, or 20% sucroglycerides in the diet for 2-years. 
Clinical observations associated with treatment were pale feces and 
poor grooming. Survival was greater among treated rats than controls. 
Treated rats showed a dose-related decrease in weight gain during the 
early part of the study, particularly in males. Weight gain then became 
similar to that of controls until the last few weeks of the study when 
control rats lost more weight than did treated rats. Alkaline 
phosphatase and SGPT levels were elevated for high dose animals until 
week 25, but were comparable to controls during weeks 51-102. No 
treatment-related changes in hematology, ophthalmoscopy, gross 
pathology, organ weights, or tumorigenesis were reported.
    6. Animal metabolism. Sucroglycerides are derived from a variety of 
21 CFR-approved edible fats and oils including, but not limited to, 
lard, tallow, palm oil, rapeseed (canola) oil, and coconut oil. Mono- 
and di-glycerides are GRAS substances 21 CFR 184.1505 and already have 
regulatory acceptance as agricultural inerts and adjuvants exempted 
from tolerance requirements (under 40 CFR 80.1001(c)), as do sucrose, 
fatty acids conforming to 21 CFR 172.860, methyl esters of edible fats 
and oils, and sucrose esters of fatty acids such as sorbitan fatty acid 
esters.
    7. Metabolite toxicology. The components of sucroglycerides and 
related substances already have regulatory acceptance as agricultural 
inerts exempted from tolerance requirements
    8. Endocrine disruption. Sucroglycerides are not derived from, nor 
contain any compounds which are known to be, or are suspected to be, 
endocrine disruptors. Sucroglycerides are derived from a variety of 21 
CFR-approved edible fats and oils including, but not limited to, lard, 
tallow, palm oil, rapeseed (canola) oil, and coconut oil. Mono- and di-
glycerides are GRAS substances 21 CFR 184.1505 and already have 
regulatory acceptance as agricultural inerts and adjuvants exempted 
from tolerance requirements (under 40 CFR 180.1001(c)), as do sucrose 
fatty acids conforming to 21 CFR 172.860, methyl esters of edible fats 
and oils, and sucrose esters of fatty acids such as sorbitan fatty acid 
esters.

B. Aggregate Exposure

    Consistent with section 408(c)(2)(B) of FFDCA, Rhodia, Inc. 
believes that, based on our prior submissions (as Rhone-Poulenc, Inc.), 
EPA now has sufficient data to assess the hazards of sucroglycerides 
and to make a determination on aggregate exposure, consistent with 
section 408(b)(2), for tolerance exemptions for the residues of 
sucroglycerides on growing crops, raw agricultural commodities after 
harvest and animals.
    1. Dietary exposure--i. From food and feed uses, drinking water, 
and non-dietary exposures. For the purposes of assessing the potential 
dietary exposure under these exemptions, Rhodia, Inc. considered that 
under these exemptions sucroglycerides could be present in all raw and 
processed agricultural commodities although, due to a lack of water 
solubility (octanol/water partition coefficient was estimated as Ko/w > 
3.38 x 106) no drinking water exposure

[[Page 36683]]

was possible. Non-occupational, non-dietary exposure is highly unlikely 
given that the inhalation potential or dermal absorption of these 
substances are not feasible. No concerns for risks associated with any 
potential exposure scenarios are reasonably foreseeable.
    ii. Sucroglycerides are derived from a variety of 21 CFR-approved 
edible fats and oils including, but not limited to, lard, tallow, palm 
oil, rapeseed (canola) oil, and coconut oil. Mono- and di-glycerides 
are GRAS substances 21 CFR.184.1505 and already have regulatory 
acceptance as agricultural inerts and adjuvants exempted from tolerance 
requirements (under 40 CFR 180.1001(c)), as do sucrose fatty acids 
conforming to 21 CFR 172.860, methyl esters of edible fats and oils, 
and sucrose esters of fatty acids such as sorbitan fatty acid esters.
    iii. Sucroglycerides derived from edible fats and oils have been 
granted Self-Affirmed GRAS status in the U.S and are approved for food 
use in Europe and by the WHO Joint Expert Committee on Foods (JECFA), 
with an Acceptable Daily Intake (ADI) of 0-20 mg/kg/day. 
Sucroglycerides are currently marketed by Rhodia, Inc. for food use. 
Sucroglycerides, including those derived from palm oil, hydrogenated 
palm oil, tallow, rapeseed oil, castor oil, and coconut oil have been 
used safely in foods in Europe since the early 1960s.
    2. Drinking water. Sucroglycerides are insoluble in water, hence 
exposure from drinking water is not considered to be a route of 
exposure.
    3. Non-dietary exposure. Non-occupational, non-dietary exposure is 
highly unlikely given that the inhalation potential or dermal 
absorption of these substances are not feasible. No concerns for risks 
associated with any potential exposure scenarios are reasonably 
foreseeable.

C. Cumulative Effects

    Section 408(b)(2)(D)(v) of FFDCA requires that, when considering 
whether to establish, modify, or revoke a tolerance or tolerance 
exemption, the Agency consider ``available information'' concerning the 
cumulative effects of a particular chemical's residues and ``other 
substances that have a common mechanism of toxicity.'' In the case of 
sucroglycerides, the lack of observed toxicity of these substances 
after acute and chronic exposure would suggest that a cumulative risk 
assessment is therefore not necessary.

D. Safety Determination

    1. U.S. population. Sucroglycerides derived from edible fats and 
oils have been granted Self-Affirmed GRAS status in the U.S and are 
approved for food use in Europe and by the WHO Joint Expert Committee 
on Foods (JECFA), with an Acceptable Dietary Intake (ADI) of 0-20 mg/
kg/day. Sucroglycerides are derived from a variety of 21 CFR-approved 
edible fats and oils including, but not limited to, lard, tallow, palm 
oil, rapeseed (canola) oil, and coconut oil. Mono- and di-glycerides 
are GRAS substances 21 CFR 184.1505 and already have regulatory 
acceptance as agricultural inerts and adjuvants exempted from tolerance 
requirements (under 40 CFR 180.1001(c)), as do sucrose, fatty acids 
conforming to 21 CFR 172.860, methyl esters of edible fats and oils, 
and sucrose esters of fatty acids such as sorbitan fatty acid esters.
    Based on these materials' low-risk profiles, there is a reasonable 
certainty that no harm to the U.S. population will result from 
aggregate exposure to sucroglycerides.
    2. Infants and children. FFDCA section 408 provides that EPA shall 
apply an additional tenfold margin of safety for infants and children 
in the case of threshold effects to account for pre- and postnatal 
toxicity and the completeness of the data base unless EPA concludes 
that a different margin of safety will be safe for infants and 
children. Margins of safety are incorporated into EPA risk assessments 
either directly through the use of margin of exposure analysis or 
through using uncertainty (safety) factors in calculating a dose level 
that poses no appreciable risk to humans.
    Due to the extensive available toxicology database including a 
reproductive toxicity study and studies of sucroglycerides in the diets 
of bottle-fed calves, and the low expected toxicity of these compounds, 
Rhodia, Inc. does not believe a safety factor analysis is necessary in 
assessing the risk of these compounds. For the same reasons we believe 
the additional safety factor is unnecessary.

E. International Tolerances

    Sucroglycerides derived from edible fats and oils are approved for 
food use in Europe and by the WHO JECFA, with an ADI of 0-20 mg/kg/day. 
Sucroglycerides are currently marketed by Rhodia, Inc. for food use. 
Sucroglycerides, including those derived from palm oil, hydrogenated 
palm oil, tallow, rapeseed oil, castor oil, and coconut oil have been 
used safely in foods in Europe since the early 1960s.
    There are no Codex Alimentarius Commission (Codex), Canadian or 
Mexican residue limits for sucroglycerides, which have been granted 
self-affirmed GRAS status in the U.S.

F. Conclusion

    Based on the information and data considered, Rhodia, Inc. proposes 
that exemption from the requirements of a tolerance be established for 
Sucroglycerides derived from 21 CFR-approved fats and oils when used in 
accordance with good agricultural practice as inert ingredients in 
pesticide formulations applied to growing crops or to raw agricultural 
commodities after harvest (under 40 CFR.180.1001(c)).

2. Rhone-Poulenc Ag Company

PP 8F4969

    EPA has received a pesticide petition (PP 8F4969) from Rhone-
Poulenc Ag Company, P.O. Box 12014, 2 T.W. Alexander Drive, Research 
Triangle Park, NC 27709. proposing pursuant to section 408(d) of the 
Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 
CFR part 180 by establishing a tolerance for residues of fosetyl-Al 
(aluminum tris(O-ethylphosphonate) in or on the raw agricultural 
commodity bananas at 3.0 parts per million (ppm). EPA has determined 
that the petition contains data or information regarding the elements 
set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 
evaluated the sufficiency of the submitted data at this time or whether 
the data supports granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of fosetyl-Al in plants is 
adequately understood. Adequate data on the nature of the residues in 
plants, including identification of major metabolites and degradates of 
fosetyl-Al, are available. Radiolabeled studies on the uptake, 
translocation and metabolism in plants show that the chemical proceeds 
through hydrolytic cleavage of the ethyl ester. The major residues are 
fosetyl-Al, phosphorus acid and ethanol. The tolerances are established 
for the parent only, that is fosetyl-Al. There is no reasonable 
expectation of residues occurring in eggs, milk, and meat of livestock 
and poultry since there are no livestock feed items associated with 
commodities treated with fosetyl-Al. Relating specifically to the 
proposed tolerance on bananas, no processed food or livestock feed 
items are associated with this commodity. Accordingly, tolerances in 
meat, animal byproducts and milk are not necessary.

[[Page 36684]]

    2. Analytical method. Adequate methods are available for 
enforcement purposes. There are two analytical methods acceptable for 
determining residues of fosetyl-Al in plants: a gas chromatography 
method is available for enforcement of tolerance in pineapple and is 
listed as Method I in PAM, Vol. II; a GC/phosphorus specific flame 
photometric detector (FPD-P) method (Rhone-Poulenc Method No. 163) for 
citrus has undergone a successful method tryout on oranges and has been 
sent to the FDA for inclusion in PAM as Method II.
    3. Magnitude of residues. Seven field sites in six Latin American 
countries were treated in two applications at the rate of 4.8 Kg/ha/
application. Two of the seven trials also included a 2x rate 
application. Applications were made by two methods: foliar spray by 
ground equipment and tree injection into the pseudostem. The 
applications were made approximately 70-days apart with a PHI of 0- 
days for the foliar treatments and 1-day for the injection treatments. 
Each plot included both bagged and unbagged bunches. Fosetyl-Al 
residues greater than the LOT were found in 22 of the 96 treated banana 
samples. Residues were highest in the 1x and 2x foliar unbagged 
treatments, averaging 0.45 ppm from the 1x treatment and 0.69 ppm from 
the 2x treatment. Residues were very low from all foliar bagged and all 
injection treatments, averaging at or below the LOT. Residues from all 
treated samples ranged from no detects to 1.99 ppm.

B. Toxicological Profile

    1. Acute toxicity. Fosetyl-Al presents a minimal acute hazard. The 
acute toxicity data support that acute exposure is unlikely to 
constitute any significant risk. A complete battery of acute toxicity 
studies for fosetyl-Al technical have been conducted. The 
LD<INF>50</INF> from the acute oral rat is 5.4 g/kg and the 
LD<INF>50</INF> from an acute dermal rabbit study is >2 g/kg. The 
LC<INF>50</INF> for a rat inhalation study is >1.73 mg/L. The acute 
oral rat and primary dermal irritation studies indicate category IV 
toxicity. A guinea pig dermal sensitization study shows fosetyl-Al is 
not a skin sensitizer. The primary eye irritation study in rabbits 
shows fosetyl-Al to be an eye irritant with Category I toxicity.
    2. Genotoxicity. Fosetyl-Al is neither mutagenic nor genotoxic. The 
genetic toxicity potential of fosetyl-Al was assessed in several 
assays. Eight mutagenicity tests performed with fosetyl-Al were 
negative. The tests included two Ames assays with S. typhimurium, two 
phase induction assays using E. coli, two micronucleus studies in mice, 
one DNA repair assay using E. coli and one mutation assay in 
Saccharomyces cereviseae.
    3. Reproductive and developmental toxicity. Fosetyl-Al is not a 
reproductive toxicant and shows no evidence of estrogenic or androgenic 
related effects. In a 3-generation reproduction study, fosetyl-Al was 
administered to rats at dietary levels of 0, 6,000, 12,000 or 24,000 
ppm. No adverse effects on reproductive performance or pup survival 
were observed in any dose group. The LEL was established at 12,000 ppm 
based on effects on animal weights and urinary tract changes. The NOEL 
for all effects was 6,000 ppm. Developmental toxicity studies were 
conducted with technical grade fosetyl-Al in rats and rabbits. These 
studies are summarized below.
    i. Rat. A teratology study in rats dosed via oral gavage at 500, 
1,000 or 4,000 mg/kg/day showed a developmental NOEL of 1,000 mg/kg. At 
4,000 mg/kg, there was maternal toxicity, as evidenced by effects on 
animal weights, maternal deaths, increased resorptions and delayed 
fetal ossification.
    ii. Rabbit. A rabbit teratology study showed no toxic effects at 
oral doses up to 500 mg/kg. Effects of fosetyl-Al on fetal development 
were observed only in the rat at a dose producing severe maternal 
toxicity. In the absence of maternal toxicity, no adverse effects on 
fetal development were observed, i.e. at 1,000 milligram/kilograms/day 
(mg/kg/day) in rats or at 500 mg/kg/day in rabbits.
    4. Subchronic toxicity. In subchronic studies, no significant 
toxicity was observed even at doses exceeding the limit of 1,000 mg/kg/
day.
    i. A 21-day dermal study in rabbits showed mild to moderate skin 
irritation and a NOEL of 1.5 g/kg/day.
    ii. A 90-day feeding study in rats showed a NOEL of >5,000 ppm; the 
LEL was 25,000 ppm with extramedullary hematopoiesis in the spleen.
    iii. A 90-day dog feeding study showed a NOEL of 10,000 ppm and a 
LEL at 50,000 ppm, at which the test animals had a lower serum 
potassium level than untreated animals.
    5. Chronic toxicity. Chronic toxicity studies have been conducted 
in dogs and rats.
    i. Dog. Fosetyl-Al was fed to dogs for 2-years at concentrations of 
0, 10,000, 20,000, and 40,000 ppm. The NOEL was 10,000 ppm, equivalent 
to 250 mg/kg/day. The LEL was 20,000 ppm based on a slight degenerative 
effect on the testes. These testicular changes, as well as a few 
scattered clinical changes, were seen in the high dose dogs. No effects 
were observed in the urinary tract.
    ii. Rat. Fosetyl-Al was administered via admixture in the diet to 
CD rats at target levels of 0, 2,000, 8,000, and 30,000/40,000 ppm for 
approximately 2-years. Based on these levels, respective doses were 
100, 400 and 2,000/1,500 mg/kg/day. After 2-weeks at 40,000 ppm, this 
dietary level was reduced to 30,000 ppm due to the occurrence of red 
coloration of the urine and a decrease in body weight gain. Although 
these findings were no longer apparent after week 2, analytical 
verification of dietary levels revealed that the highest dietary level 
ranged from approximately 38,000 to 61,000 ppm during the first 32 
weeks of the study. No significant differences in bwt or food 
consumption were noted at 2,000 or 8,000 ppm. No biologically 
significant differences were observed in ophthalmoscopy, hematology, 
clinical chemistry, or urinalysis for treated and control animals. 
Calculi in the urinary bladder were observed for several male and 
female rats in the high dose group. Non-neoplastic findings consisted 
of epithelial hyperplasia and inflammation in the urinary bladders of 
males at 30,000/40,000 ppm. Increased incidences of hydronephrosis, 
inflammation, and epithelial hyperplasia in the kidney were also 
observed in males from the high dose group. Females from the same group 
exhibited increased incidences of epithelial hyperplasia in the urinary 
bladder and hydronephrosis in the kidney. The NOEL in the chronic rat 
study was 8,000 ppm (400 mg/kg/day).
    iii. Conclusion. The lowest NOEL for chronic effects of fosetyl-Al 
is 10,000 ppm (250 mg/kg/day) based on the dog study. This NOEL is 
based on minor changes at 20,000 ppm. In the rat, calculi in the 
urinary bladder and related histopathological changes in the bladder 
and kidneys of males and females were observed at 30,000/40,000 ppm.
    6. Carcinogenicity. Long-term feeding studies were conducted with 
technical grade fosetyl-Al in mice and rats and with monosodium 
phosphite, the primary urinary metabolite of fosetyl-Al, in rats. These 
studies, in addition to a mechanistic study in rats, are described 
below:
    i. Rat. Fosetyl-Al was administered via admixture in the diet to CD 
rats at target levels of 0, 2,000, 8,000, and 30,000/40,000 ppm for 
approximately 2-years. After 2-weeks at 40,000 ppm, this dietary level 
was reduced to 30,000 ppm due to the occurrence of red coloration of 
the urine and a decrease in body weight gain. Although these findings 
were no longer apparent after week 2,

[[Page 36685]]

analytical verification of dietary levels revealed that the highest 
dietary level ranged from approximately 38,000 to 61,000 ppm during the 
first 32 weeks of the study. Calculi in the urinary bladder were 
observed for several male and female rats at 30,000/40,000 ppm. 
Microscopic examination revealed transitional cell carcinomas and 
papillomas in the urinary bladders of high dose males. In addition, a 
statistically significant increase in adrenal pheochromocytomas (benign 
and malignant combined) was observed in males at 8,000 and 30,000/
40,000 ppm. The adrenal slides were independently reread by two 
consulting pathologists who found no significant dose-related increases 
in the incidence of pheochromocytomas or hyperplasia. The NOEL for 
fosetyl-Al in the chronic rat study was 8,000 ppm. A subsequent 
mechanistic study in rats conducted with dietary levels of 8,000, 
30,000 and 50,000 ppm demonstrated that the massive doses of 30,000 and 
50,000 ppm fosetyl-Al alter calcium/phosphorous homeostasis resulting 
in severe acute renal injury, similar to that observed in the chromic 
rat study, and the formation of calculi in kidneys, ureters, and 
bladder. Under conditions of chronic exposure, these effects could lead 
to the formation of bladder tumors as seen in the chronic rat study. At 
8,000 ppm, no evidence of renal injury was observed, a result 
consistent with the absence of bladder tumors. Thus, the bladder tumors 
induced by fosetyl-Al were the result of acute renal injury followed by 
a chronic toxic reaction rather than a true carcinogenic effect. An 
oncogenicity study in rats was conducted with monosodium phosphite 
administered via dietary mixture at levels of 2,000, 8,000, and 32,000 
ppm. No evidence of oncogenicity was observed in this study.
    ii. Mouse. A 2-year feeding/carcinogenicity study was conducted in 
mice fed diets containing fosetyl-Al at 0, 2,500, 10,000, or 20,000/
30,000 ppm. The 20,000 ppm dose was increased to 30,000 ppm during week 
19 of the study. The NOEL for all effects was 20,000/30,000 ppm (3,000/
4,500 mg/kg/day). There were no carcinogenic effects observed under the 
conditions of this study.
    iii. Conclusion. The Office of Pesticide Programs', Health Effects 
Division, Carcinogenicity Peer Review Committee (CPRC) concluded in 
their report of June 29, 1993 that the pesticidal use of fosetyl-Al is 
unlikely to pose a carcinogenic hazard for humans given that:
    a. Tumors develop in rats under extreme conditions that are 
unlikely to be achieved other than under laboratory conditions (at a 
dose in excess of the OPP dose limit for carcinogenicity studies).
    b. Tumors in rats are believed to develop only at doses that 
produce stones.
    c. Human dietary exposure to fosetyl-Al is only about one-
500,000<SUP>th</SUP> of the NOEL for stone formation in the rat (the 
most sensitive experimental model).
    d. The dose of fosetyl-Al which can be absorbed dermally by 
applicators is also probably too low to result in stone formation. EPA 
has therefore chosen to use the Reference Dose (RfD) to quantify 
dietary risk to humans.
    7. Neurotoxicity. No evidence of neurotoxic potential has ever been 
observed with fosetyl-Al. Fosetyl-Al does not have a chemical function 
associated with neurotoxicity. No signs of neurotoxicity have been 
recorded in any study conducted with fosetyl-Al.
    8. Animal metabolism. Rat metabolism studies showed that most of 
the radiolabel rapidly appeared in exhaled carbon dioxide. There was 
also some radiolabel excreted in the urine as phosphite, along with a 
smaller amount as the unchanged parent compound. It appears that 
fosetyl-Al is essentially completely absorbed after ingestion and 
extensively hydrolyzed to carbon dioxide which is exhaled. The 
phosphite is excreted in the urine without further oxidation to 
phosphate. Aluminum does not appear to be absorbed to a significant 
extent from the gastrointestinal tract.
    9. Metabolite toxicology. There are no metabolites of toxicological 
concern. The tolerances are established for the parent only, that is 
fosetyl-Al.
    10. Endocrine disruption. No evidence of estrogenic or androgenic 
effects were noted in any study with fosetyl-Al. No adverse effects on 
mating or fertility indices and gestation, live birth, or weaning 
indices were noted in a 3-generation rat reproduction study at doses 
well above EPA's limit of 1,000 mg/kg/day. Therefore, fosetyl-Al does 
not have any effect on the endocrine system.

C. Aggregate Exposure

    1. Dietary exposure--i. Chronic risk. Based upon all available 
data, EPA has established an RfD of 3.0 mg/kg/day using a 100 fold 
safety factor to account for inter- and intra-species differences and a 
NOEL of 250 mg/kg/bwt/day from a 2-year feeding study in dogs. A 
chronic dietary risk assessment was prepared using established and 
proposed tolerance residue levels, 1987 food consumption data, and 100% 
crop treated. The calculated potential exposure for the U.S. population 
is 0.065760 mg/kg bwt/day. Potential exposure for nursing and non-
nursing infants less than 1-year old, children aged 1 to 6-years, and 
children aged 7 to 12-years is calculated to be 0.022485, 0.134076, 
0.116682, and 0.069637 mg/kg bwt/day, respectively. This results in 
utilization of 2.2, 4.5, 3.9, and 2.3% of the RfD for the whole U.S. 
population, non-nursing infants less than 1-year old, children aged 1 
to 6- years, and children aged 7 to 12-years, respectively. Thus, the 
dietary exposure for fosetyl-Al is well below the RfD of 3.0 mg/kg/day 
and is negligible for all segments of the population including infants 
and children.
    ii. Acute risk. Based on a lack of acute toxicity and the large 
margins of exposure in the chronic dietary assessment, fosetyl-Al does 
not pose any acute dietary risks.
    2. Food. The dietary exposure assessment accounts for all 
anticipated dietary exposure for a tolerance of 3.0 ppm on bananas, 
which is the subject of this request, and all other active and pending 
tolerances for fosetyl-Al. The active tolerances are for asparagus, 
avocados, blueberries, brassica, caneberries, citrus, cucurbits, 
ginseng, hops (dried), leafy vegetables, pineapple, onions (dry bulb), 
pome fruit, strawberries, and tomatoes. Pesticide petitions proposing 
the establishment of tolerances for Fosetyl-Al on grapes and macadamia 
nuts (IR-4) have also been submitted to the Agency.
    3. Drinking water. There is no established maximum contaminant 
level (MCL) or health advisory level (HAL) for fosetyl-Al. The 
potential for ground water and/or surface water contamination by 
fosetyl-Al and its degradates is expected to be very low, in most 
cases, due to the rapid degradation of the compound in soil to non-
toxic degradates under both aerobic and anaerobic conditions. Under 
aerobic laboratory conditions, the half-life of fosetyl-Al is between 1 
and 1.5 hours in loamy sand, silt loam, and clay loam and 20 minutes in 
sandy loam soil. The degradation proceeds through the hydrolysis of the 
ethyl ester bond, resulting in the formation of phosphorous acid and 
ethanol. The ethanol is further degraded into carbon dioxide. Based on 
the short half-life of fosetyl-Al and the known fate of phosphates 
under anaerobic conditions, EPA determined that an anaerobic soil 
metabolism study was not necessary. An anaerobic aquatic soil 
metabolism study was conducted. When anaerobic conditions were 
established by flooding soil, the half-life was 40 hours with silty

[[Page 36686]]

clay loam, and 14 hours with sandy loam soil.
    4. Non-dietary exposure. In addition to agricultural uses, fosetyl-
Al is registered on ornamentals and turf under the brand names 
CHIPCO<SUP></SUP> Aliette<SUP></SUP> WDG, and Aliette<SUP></SUP> HG. 
CHIPCO<SUP></SUP> Aliette<SUP></SUP> WDG is sold to professional 
applicators only, which includes lawn care operators (LCO). All 
residential uses of CHIPCO<SUP></SUP> Aliette<SUP></SUP> WDG are 
applied by an LCO. Typically, LCOs use fungicides for ornamentals and 
turf on an as needed basis only in part because of high cost, variable 
performance, and little residual control. In 1994, LCOs made an 
estimated 206,200 acre treatments in total for all fungicides 
representing less than 1% of the available acreage of 32,740,000 
assuming each acre was treated once (Kline & Company, Inc.). 
CHIPCO<SUP></SUP> Aliette<SUP></SUP> WDG is estimated to have been used 
on less than 3% of the acres treated with commercial landscapes (turf 
and ornamentals) constituting the majority of the use by LCOs. 
Therefore, fosetyl-Al is used by LCOs on less than 0.03% of the total 
available acres. Aliette HG is not currently being sold but plans are 
to introduce this product on the market in 1998 on a limited 
geographical scale. The product will be available to the home consumer 
in single dose packages for residential use on turf and ornamentals. 
Available market research information indicates that a total of 1.7 
million pounds fungicide (active ingredient) are sold annually for use 
by the home owner. Since Aliette HG will just be entering the market, 
only very small quantities of the product are expected to be sold. The 
maximum amount expected to be sold for the next few years is 
approximately 1% of the total 1.7 million pounds of fungicide products 
available to the home owner for residential use on turf and 
ornamentals. This use of the product is therefore expected to have a 
negligible impact on the aggregate exposure for fosetyl-Al.
    5. Conclusion. Considering that fosetyl-Al is applied by LCOs on 
about 0.03% of available lawn acres (the majority being commercial 
landscapes), the likelihood of post application exposure occurring, 
particularly in a residential situation, is extremely low. The use of 
fosetyl-Al by the homeowner constitutes a minor use of the product 
since only small quantities are expected to be sold in 1998. Other 
applications by professional operators, e.g. golf courses, nurseries, 
sod farms, present only very limited exposure to a limited population 
of adults but do not pose any exposure to small children. Thus, the 
ornamental and turf uses are not expected to add significantly to the 
aggregate exposure for fosetyl-Al, and only dietary exposure has been 
taken into consideration for risk assessment purposes.

D. Cumulative Effects

    Effects associated with fosetyl-Al are unlikely to be cumulative 
with any other compound. The formation of calculi and bladder tumors in 
rats is the only significant toxicological effect observed with 
fosetyl-Al. These effects were observed in rat only at a dose which not 
only exceeds estimated human exposure by several orders of magnitude 
but is in excess of the OPP dose limit for carcinogenicity studies. 
Therefore, an aggregate assessment based on common mechanisms of 
toxicity is not appropriate as exposure to humans will be well below 
the levels producing calculi and bladder tumors in rats. Further, 
considering the rapid elimination of fosetyl-Al in the rat metabolism 
study, any effects associated with fosetyl-Al are unlikely to be 
cumulative with any other compound. Based on these reasons, only the 
potential risks of fosetyl-Al are considered in the exposure 
assessment.

E. Safety Determination

    1. U.S. population. Based upon all available data, EPA has 
established an RfD of 3.0 mg/kg/day using a 100 fold safety factor to 
account for inter- and intra-species differences and a NOEL of 250 mg/
kg bwt/day from a 2-year feeding study in dogs. A chronic dietary risk 
assessment using established and proposed tolerance residue levels, 
1987 food consumption data, and 100% crop treated results in 
utilization of 2.2, 4.5, 3.9, and 2.3% of the RfD for the whole U.S. 
population, non-nursing infants less than 1-year old, children aged 1 
to 6-years, and children aged 7 to 12-years, respectively. Thus, the 
dietary exposure for fosetyl-Al is well below the RfD of 3.0 mg/kg/day 
and is negligible for all segments of the population including infants 
and children.
    2. Infants and children--Adequate margin of safety. In assessing 
the potential for additional sensitivity of infants and children to 
residues of fosetyl-Al, the available developmental and reproductive 
toxicity studies and the potential for endocrine modulation were 
considered. Developmental toxicity studies in two species indicate that 
fosetyl-Al has no teratogenic potential at any dose level. Further, no 
adverse effects on fetal development were observed in rabbits at doses 
up to 500 mg/kg/day or in rats at doses up to 1,000 mg/kg/day. In a 3-
generation rat reproduction study, no adverse effects on reproductive 
performance or pup survival were observed up to 24,000 ppm (equivalent 
to a dose well above EPA's limit dose of 1,000 mg/kg/day). Maternal and 
developmental NOELs and LELs were comparable in all studies indicating 
no increase in susceptibility of developing organisms. Further, 
fosetyl-Al has no endocrine-modulation characteristics as demonstrated 
by the lack of endocrine effects in developmental, reproductive, 
subchronic, and chronic studies. Since registration of fosetyl-Al in 
1983, EPA has assessed the safety of this molecule several times and 
has concluded repeatedly that the level of dietary exposure is 
sufficiently low to provide ample margins of safety to guard against 
any potential adverse effects of fosetyl-Al. Considering the 
conservative exposure assumptions in setting the tolerances and the 
dietary risk assessment assuming 100% crop treated, less than 5% of the 
RfD is utilized for non-nursing infants less than 1-year old, children 
aged 1 to 6-years, and children aged 7 to 12-years. The probability of 
non-occupational sources of exposure to fosetyl-Al is negligible. 
Therefore, based upon the completeness and reliability of the toxicity 
data and the conservative exposure assessment, there is a reasonable 
certainty that no harm will result to infants and children from 
exposure to the residues of fosetyl-Al and no additional uncertainty 
factor is warranted.

F. International Tolerances

    There are presently no Codex maximum residue levels established for 
residues of fosetyl-Al on any crop.
[FR Doc. 98-17808 Filed 7-6-98; 8:45 am]
BILLING CODE 6560-50-F


</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>